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26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
26.09 metformain as a antiaterosceoti
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26.09 metformain as a antiaterosceoti

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  • The United Kingdom Prospective Diabetes Study (UKPDS) randomized patients with newly diagnosed type 2 diabetes to metformin (n = 342; target fasting glucose of 108 mg/dL), other hypoglycemic medication (either chlorpropamide, glibenclamide, or insulin) (n = 951; target fasting glucose of 108 mg/dL), or usual care (n = 411). 1 The median duration was 10.7 years. • Relative to usual care, metformin was associated with a 36% relative risk reduction in all-cause mortality (RR, 0.64, 95% CI, 0.45–0.91). The other intensive treatments combined were associated with an 8% relative risk reduction (RR, 0.92; 95% CI, 0.71–1.18) (P = 0.021, comparison between the two intensive-treatment groups). 1 • There was no difference between the two intensive-treatment groups in the relative risk reductions in stroke and MI, although the trend was in favor of metformin. • These data suggest that insulin-sensitizing therapy may be associated with greater reductions in CV outcomes than other hypoglycemic therapies. 1. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854-865.
  • This graph compares these to other recent IVUS regression-progression trials. Notably, the glimepiride treatment group (shown in blue) progressed at a rate close to what would be expected for the achieved level of LDL. This suggests a neutral effect for glimepiride on disease progression. However, the pioglitazone group (shown in orange) had substantially less progression than would have been predicted for the LDL level achieved, suggesting an anti-atherosclerotic effect.
  • Zhonghua Yi Xue Za Zhi. 2009 Aug 11;89(30):2134-7. [Primary preventive effect of metformin upon atherosclerosis in patients with type 2 diabetes mellitus]. [Article in Chinese] Zhang XY, Du JL, Jia YJ, Bai R, Yang Y, Ba Y, Xing Q, Men LL. Source Department of Endocrinology, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China. Abstract OBJECTIVE: To investigate the preventive action of metformin for atherosclerosis (AS) in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 140 cases with T2DM were assigned to 2 groups taking metformin (n = 75) or not (n = 65). All cases received intensive control of blood glucose, blood pressure and blood lipids for 100 weeks. The data before and after intensive control were recorded and statistically analyzed. Common carotid intima-media thickness (CC-IMT) was the efficacy endpoint of AS. RESULTS: Diastolic blood pressure (DBP), fasting blood glucose, post 2-hour blood glucose, glycated hemoglobin A1c, triglyceride (TG) and total cholesterol (TC) decreased in both groups after intensive metabolic control for 100 weeks (P < 0.05). Body mass index (BMI), HOMA insulin resistance index (HOMA-IR) and CC-IMT decreased in metformin group (P < 0.05) while high-density lipoprotein cholesterol (HDL-C) increased (P < 0.05). BMI (23.1 +/- 0.98) kg/m2, HOMA-IR (1.68 +/- 0.20) and CC-IMT (0.55 +/- 0.13) mm in metformin group were lower than those in non-metformin group [(24.1 +/- 0.05) kg/m2, 2.03 +/- 1.38, (0.70 +/- 0.15) mm)] at 100 week (P < 0.05). CC-IMT was positively correlated with BMI (r = 0.489, P < 0.05) , TC (r = 0.429, P < 0.05), low-density lipoprotein cholesterol (LDL-C) (r = 0.426, P < 0.05) and HOMA-IR (r = 0.428, P < 0.05). CONCLUSION: Metformin attenuates CC-IMT of patients with T2DM and it has the primary preventive effect upon AS in patients with T2DM.
  • • Another class of insulin sensitizer, metformin, was associated with a 14% relative risk reduction in mortality (HR, 0.86; 95% CI, 0.78–0.97; data not shown). 1 1. Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: An observational study. Circulation. 2005;111:583-590.
  • Data presented are differences between the percent increases in forearm blood flow measured in response to infusions of vasodilator substances measured before and after treatment with metformin or placebo
  • Transcript

    • 1. METFORMIN RENAISSANCE A NEW ANTI ATHEROSCLEROTIC DRUG Dr. Rajeev Agarwala Director of Cardiology Services Jaswant Rai Speciality Hospital, Meerut. E-mail: rajeev_jrsh@yahoo.co.in
    • 2. WHY CARDIOLOGISTWHY CARDIOLOGIST SHOULD TALK DIABETES?SHOULD TALK DIABETES? WHY CLINICIANS SHOULDWHY CLINICIANS SHOULD USE METFORMIN?USE METFORMIN? WHY METFORMIN WORKS?WHY METFORMIN WORKS?
    • 3. QUESTIONQUESTION NO. 1NO. 1
    • 4. IN DIABETES, VASCULAR DISEASEIN DIABETES, VASCULAR DISEASE BEGINS EARLYBEGINS EARLY Insulin Resistance precedes overt Hyperlycemia or Diabetes Newly diagnosed Diabetics have Vascular Disease at Presentation
    • 5. DIABETIC ATHEROMADIABETIC ATHEROMA A DIFFERENT DISEASEA DIFFERENT DISEASE
    • 6.  Aim & objective:Aim & objective:  Several studies have shown that T2DM isSeveral studies have shown that T2DM is associated with progressive atherosclerosis,associated with progressive atherosclerosis, resulting in increased risk of CV events.resulting in increased risk of CV events.  The typical characteristic progression of coronaryThe typical characteristic progression of coronary plaques in patients with T2DM was evaluatedplaques in patients with T2DM was evaluated using integrated backscatter intravascularusing integrated backscatter intravascular ultrasound (IB-IVUS) examinationultrasound (IB-IVUS) examination Eur Heart Jn Cardvs Imag Feb 2012
    • 7. PERCENT CHANGE IN CONVENTIONALPERCENT CHANGE IN CONVENTIONAL AND IB-IVUS PROFILES DURING 6AND IB-IVUS PROFILES DURING 6 MONTH FOLLOW-UPMONTH FOLLOW-UP Eur Heart Jn Cardvs Imag Feb 2012
    • 8. Eur Heart Jn Cardvs Imag Feb 2012
    • 9. THE ENDOTHELIUM: A BIOLOGICALLY ACTIVE, DYNAMIC ORGAN
    • 10. QUESTIONQUESTION NO. 2NO. 2
    • 11. DRUG THERAPYDRUG THERAPY
    • 12. So….So…. Br J Diabetes Vasc Dis. 2007;7:204-210
    • 13. UK Prospective Diabetes StudyUK Prospective Diabetes Study 20-year Interventional Trial from 1977 to 1997  5,102 patients with newly-diagnosed DM2  Median follow-up 10.0 years, range 6 to 20 years  Results presented in 1998 10-year Post-Trial Monitoring from 1997 to 2007  Annual follow-up of the survivor cohort  Clinic-based for first five years  Questionnaire-based for last five years Median overall follow-up 17.0 years, range 16 to 30 years
    • 14. UKPDS 80. NEJM 2008; 359: 1577-89 UKPDS 34. Lancet 1998; 352: 854-65 Diabetes-related deaths All –Cause Mortality Myocardial Infarction CV Complications reduced and Survival increased versus other therapies POST-Trial Monitoring 1997 - 2007 -30% -27% -33% -42% -36% -39% UKPDS Trial Intervention 1977 - 1997 CV Complications reduced and Survival increase maintained Lessons from UKPDS 10-year Follow-up:Lessons from UKPDS 10-year Follow-up: “Legacy Effect ” or “Metabolic Memory” of Earlier“Legacy Effect ” or “Metabolic Memory” of Earlier Metformin TherapyMetformin Therapy
    • 15. HbA1c Microvascular complications e.g. kidney disease and blindness * Heart attack * HbA1cHbA1cHbA1cHbA1c Deaths related to diabetes * 21% Stratton IM et al. UKPDS 35. BMJ 2000; 321: 405–412 Amputation or fatal peripheral blood vessel disease * 37% 14% 12% 43% Stroke ** 1% Epidemiological extrapolation showing benefit of a 1% reduction in mean HbA1c * p<0.0001 ** p=0.035
    • 16. UKPDS 34: CV Risk Reduction with Metformin N = 4075 with type 2 diabetes UKPDS 34 Group. Lancet. 1998;352:854-65. Favors metformin or intensive Favors conventional All-cause mortality Metformin Intensive Myocardial infarction Metformin Intensive Stroke Metformin Intensive 0.021 0.021 0.021 Aggregate endpoints P* 0.1 1 10 Intensive = HbA1c < 7% Conventional = HbA1c < 7.9% Relative risk reduction (95% CI) 36
    • 17. Arch Intern Med. 2010;170(21):1892-1899
    • 18. STUDY BACKGROUND  Metformin is recommended in T2DM because itMetformin is recommended in T2DM because it reduced mortality among overweightreduced mortality among overweight participants in the UKPDS (beyond its glycemicparticipants in the UKPDS (beyond its glycemic benefits) when used mainly as a means ofbenefits) when used mainly as a means of primary prevention.primary prevention.  However, Metformin is often not considered inHowever, Metformin is often not considered in patients with CV conditions because of concernspatients with CV conditions because of concerns about its safety.about its safety. Arch Intern Med. 2010;170(21):1892-1899
    • 19. REACH Registry Metformin Study Methods  Assessed whether Metformin use was associated with a difference in mortality among patients with atherothrombosis.  The study sample comprised 19 691 (out of 68375 patients) patients having diabetes with established atherothrombosis participating in the Reduction of Atherothrombosis for Continued Health (REACH) Registry between December 1, 2003, and December 31, 2004, treated with or without metformin  Out of 19691 patients, total 7457 patients had used metformin  Multivariable adjustment and propensity score were used to account for baseline differences.  The main outcome measure was 2-year mortality. Arch Intern Med. 2010;170(21):1892-1899
    • 20. Metformin use as 20 Prevention & Mortality Reduction in Patients with Diabetes Arch Intern Med. 2010;170(21):1892-1899  The mortality rates were 6.3% with metformin & 9.8% without metformin;  Adjusted Hazard Ratio (HR) was 0.76 (P.001)
    • 21. Arch Intern Med. 2010;17021):1892-1899 Metformin use & All-cause mortality: CHF Sub-group Of 4585 patients with a history of CHF,1428 were prescribed metformin. Metformin use was associated with lower all-cause mortality after adjusting for prognostic factors and propensity score (HR, 0.69; 95% CI, 0.54-0.90; P=.006)
    • 22. REACH for metformin to reduce deaths inREACH for metformin to reduce deaths in patients with diabetes and Atherothrombosispatients with diabetes and Atherothrombosis  Metformin showed - 24% reduced mortalityMetformin showed - 24% reduced mortality  These are very interesting results from an observational study. IThese are very interesting results from an observational study. I think it's fascinating.think it's fascinating.  Certainly, metformin appears to be very favorable with an impactCertainly, metformin appears to be very favorable with an impact on mortality.on mortality. In patients with diabetes and documented Atherothrombosis, the use of metformin was associated with a significant 24% reduction in all-cause mortality after two years of follow-up, according to a subgroup analysis from a large registry study presented at the American Diabetes Association (ADA) 2010 Scientific Sessions. In patients with diabetes and documented Atherothrombosis, the use of metformin was associated with a significant 24% reduction in all-cause mortality after two years of follow-up, according to a subgroup analysis from a large registry study presented at the American Diabetes Association (ADA) 2010 Scientific Sessions.
    • 23. METFORMIN USE IS ASSOCIATED WITH LOWER ALL-CAUSE MORTALITY Arch Intern Med. 2010;170(21):1892-1899 Metformin use was associated with lower all-cause mortality (HR, 0.76; 95% CI, 0.65-0.89; P.001)
    • 24. Hazard Ratio for Mortality withHazard Ratio for Mortality with Metformin in selected sub-groupsMetformin in selected sub-groups
    • 25. Results: Survival Benefit with Metformin • At 2-yr follow-up, 15.8% of patients receiving metformin & 25.5% patients not receiving metformin had died. • Patients hospitalized with HF (11.5% vs 16.4%) & hospitalized for any cause (40.9% vs 47.9%) were lower in patients receiving metformin compared to those not on met therapy over 2 yr of follow-up. Circ Heart Fail. 2011;4:53-58
    • 26. TRIAL DISCUSSION • Several potential mechanisms beyond glycemic control through which metformin may improve outcomes in HF patients. • Metformin is associated with reduction in weight gain & improvement in measures of insulin resistance. • In addition, it has been associated with improvements in endothelial function, lipoprotein metabolism, oxidative stress & abnormalities in coagulation. • These mechanisms contribute to the reduction in macrovascular events in patients on metformin therapy. Thus……. In a cohort of patients with Diabetes & HF, Metformin was associated with a survival benefit over 2 yr of follow-up Circ Heart Fail. 2011;4:53-58
    • 27. BARI 2 D Summarizes -BARI 2 D Summarizes -  A strategy of prompt coronary revascularization in patients who had been treatedA strategy of prompt coronary revascularization in patients who had been treated with intensive medical therapy for diabetes and stable ischemic disease did notwith intensive medical therapy for diabetes and stable ischemic disease did not significantly reduce the rate of death from any cause or of major cardiovascularsignificantly reduce the rate of death from any cause or of major cardiovascular events.events.  Insulin sensitization and insulin provision also had similarInsulin sensitization and insulin provision also had similar cardiovascular outcomes during a 5-year period.cardiovascular outcomes during a 5-year period.  Among patients for whom CABG was deemed to be the appropriate treatment,Among patients for whom CABG was deemed to be the appropriate treatment, prompt revascularization reduced the rate of major cardiovascular events, asprompt revascularization reduced the rate of major cardiovascular events, as compared with medical therapy, particularly among patients who were assigned tocompared with medical therapy, particularly among patients who were assigned to receive insulin sensitization.receive insulin sensitization.  In the PCI stratum, however, revascularization did not reduce the rate of death orIn the PCI stratum, however, revascularization did not reduce the rate of death or major cardiovascular events when added to medical therapy.major cardiovascular events when added to medical therapy. N Engl J Med 2009;360:2503-15.
    • 28. Rates of Survival and Freedom from Major Cardiovascular Events. There was no significant difference in rates of survival between the revascularization group and the medical-therapy group (Panel A) and between the insulin-sensitization group and the insulin-provision group (Panel B). The rates of major cardiovascular events (death, myocardial infarction, or stroke) also did not differ significantly between the revascularization group and the medical-therapy group (Panel C) or between the insulin- sensitization group and the insulin-provision group (Panel D) N Engl J Med 2009;360:2503-15.
    • 29.  200 type 2 diabetic patients post CABG200 type 2 diabetic patients post CABG received insulin infusion+metformin 1 gmreceived insulin infusion+metformin 1 gm twice daily vs control group with only insulin.twice daily vs control group with only insulin.  Lactate level, pH, base excess, blood glucoseLactate level, pH, base excess, blood glucose and serum creatinine were measured over fiveand serum creatinine were measured over five 12 h periods.12 h periods.
    • 30. METFORMIN USE IN SURGICALMETFORMIN USE IN SURGICAL PROCEDURESPROCEDURES  A recent evaluation of metforminA recent evaluation of metformin indicated that the inadvertent failure toindicated that the inadvertent failure to stop metformin before cardiac surgerystop metformin before cardiac surgery did not increase mortality and morbidity.did not increase mortality and morbidity. Anesth Analg 2007;104:42-50
    • 31. 0 100 200150 25050 Days of Follow-up Proportionevent-freea 0.5 0.6 0.7 0.8 0.9 1.0 Metformin therapy n = 887 Other therapy n =1110 METFORMIN EFFECT ON CLINICAL OUTCOMES AFTER CORONARY INTERVENTION Kao et al. Am J Cardiol 2004; 93: 1347-50 a From either revascularisation, MI or death Kaplan - Meier analysis, p = 0.005 Death 1% 3%* All MI 1% 3%* Revasc 20% 22% Single Endpoints Metformin Other
    • 32. Metformin attenuates progression of carotid arterial wall thickness in patients with type 2 diabetes Diabetes Res Clin Pract. 2004;64(3):225-8. Metformin Control 0 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.02 0.07 ChangeinCCA-IMT(mm) N = 36 Study Duration: 2 yrs CCA-IMT: Common Carotid Artery Intima Media Thickness
    • 33. Improved Cardiovascular outcomes withImproved Cardiovascular outcomes with Metformin in T2DMMetformin in T2DM 61 STUDY MAIN FINDINGS Randomized Trials UKPDS 34 Reduced risk of macrovascular diabetic complications Kooy et al Reduced risk of composite of macrovascular events Observational Studies PRESTO Reduced risk of any clinical outcome, MI, Death Johnson et al 40% reduction in risk of death Reduced risk of mortality, hospitalization, cardiovascular death Eurich et al 30% reduction in risk of death, 17% reduction in risk of death or hospitalization Evans et al 3.7 fold lower risk of cardiovascular mortality Clifford J Bailey, Ian W Campbell, Metformin: The gold standard
    • 34. The Final Endorsement for Metformin in Vascular Protection…
    • 35. Metformin Benefits Enlisted in theMetformin Benefits Enlisted in the Cochrane ReviewCochrane Review  Intensive metformin seems to reduce the risk for any clinicalIntensive metformin seems to reduce the risk for any clinical endpoint related to diabetes, death related to diabetes, allendpoint related to diabetes, death related to diabetes, all cause mortality & myocardial infarction.cause mortality & myocardial infarction.  Patients assigned to receiving metformin monotherapyPatients assigned to receiving metformin monotherapy showed a significant reduction from baseline for HbA1c,showed a significant reduction from baseline for HbA1c, BMI/weight, cholesterol, LDL-c, TGs, insulin, DBP &BMI/weight, cholesterol, LDL-c, TGs, insulin, DBP & increasing HDL-c.increasing HDL-c.  Thus, tight glycaemia control with metformin monotherapy isThus, tight glycaemia control with metformin monotherapy is one of the main therapeutic options in the type 2 diabetesone of the main therapeutic options in the type 2 diabetes mellitus in patients with overweight or obesitymellitus in patients with overweight or obesity
    • 36. Metformin Superior to Glipizide for reducingMetformin Superior to Glipizide for reducing CVD events in Diabeticd with CADCVD events in Diabeticd with CAD  Significant 52% relative risk reduction.(70% statin usage)Significant 52% relative risk reduction.(70% statin usage)  Reduces markers of inflammation, reduces vascularReduces markers of inflammation, reduces vascular adhesion molecules,reduces coagulationadhesion molecules,reduces coagulation parameters,reduces endothelial dysfunction.parameters,reduces endothelial dysfunction. -Hong J et. al.-Hong J et. al. Diabetes Care 2012 ;Diabetes Care 2012 ;1010thth DecemberDecember..
    • 37. Improved Lipoprotein Lipase mass & LDL Particle Size Diabetes Res Clin Pract. 2007;78(1):34-41. Thus, metformin may diminish insulin resistance and increase LPL production, increasing LDL particle size as a result. Metformin, increased preheparin Lipoprotein Lipase (LPL) mass levels accompanied by enlargement of LDL particle.
    • 38. PROPOSED RECOMMENDATIONSPROPOSED RECOMMENDATIONS FOR METFORMIN USE BASED ONFOR METFORMIN USE BASED ON eGFReGFR
    • 39. QUESTIONQUESTION NO. 3NO. 3
    • 40. MECHANISMMECHANISM
    • 41. Improvement in Endothelium dependantImprovement in Endothelium dependant vasodilatationvasodilatation Wuffele MG., et al. Journal of Internal Medicine , 256, 1 - 14 77
    • 42. Improved Fibrinolysis Gregorioet al., Diabetic medicine, 16, 1016 - 1024 Decreased PAI-1 activity & increased tPA activity
    • 43. Effect of Metformin Therapy on Various CV Risk Factors Administration of metformin improved glycemic control and led to a decrease in several CVD risk factors in patients with type 2 diabetes. FFA: Free Fatty Acid RLP-c: remnant lipoprotein cholesterol Metabolism. 2004;53(2):159-64.
    • 44. Effects of Metformin on Lipids: Data from Experimental Studies • Metformin reduces lipid accumulation in macrophages.1 • Metformin has demonstrated efficacy in protecting HDL from glycation-induced impairment.2 • Metformin has anti-inflammatory effects on endothelial cells through TNF-α-induced inhibitory action.3 • Additional mechanisms for the atheroprotective effect of metformin include inhibition of cellular events involved in atherogenesis such as • Leukocyte-endothelial interaction, • Foam cell formation, smooth muscle cell proliferation & • Platelet aggregation.4 1. Biochem Biophys Res Commun. 2010;393(1):89-94. 2. Atherosclerosis.2009;206(2):434-8. 3. Int J Cardiol. 2009;134(2):169-75.  4. Diabetes Metab. 2003;29:6S71-6S76
    • 45. Effect on Lipid ProfileEffect on Lipid Profile Wuffele MG., et al. Journal of Internal Medicine , 256, 1 - 14 83
    • 46. Genetic targets in lipid modulationGenetic targets in lipid modulation  Possible gentic targets of metformin inPossible gentic targets of metformin in modulation of lipids includemodulation of lipids include  Hepatic orphan nuclear receptor small heterodimerHepatic orphan nuclear receptor small heterodimer partner (SHP)partner (SHP)  Hepatic nuclear factor (hnf)-4aHepatic nuclear factor (hnf)-4a  Forkhead transcription factor (fox) 01 and foxa2Forkhead transcription factor (fox) 01 and foxa2  Ampactivated protein kinase (AMPK)Ampactivated protein kinase (AMPK) Gerald H. Tomkin; The effect of antidiabetic drugs on genes regulating lipid metabolism; Current Opinion in Lipidology 2009, 20:10–16
    • 47. ““Metformin – a Vascular drug”Metformin – a Vascular drug” • Antihypertensive effect demonstrated in animals and humansAntihypertensive effect demonstrated in animals and humans • Mechanisms involved complex:Mechanisms involved complex: – Calcium flux modulation, nitric oxide and central regulationCalcium flux modulation, nitric oxide and central regulation – Anti-glycating properties and in turn reducing oxidativeAnti-glycating properties and in turn reducing oxidative stressstress – Impressive anti-apoptotic actionsImpressive anti-apoptotic actions Br J Diabetes Vasc Dis. 2007;7:204-210
    • 48. Latest ADA-EASD Position Statement:Latest ADA-EASD Position Statement: Importance of Cardiovascular risk reductionImportance of Cardiovascular risk reduction Comprehensive cardiovascular risk reduction must be a major focus of therapy. Diabetes Care. Published ahead of print. April 19; 2012
    • 49. RECOMMENDATIONS ONRECOMMENDATIONS ON DIABETES MELLITUSDIABETES MELLITUS Joint ESC Guidelines-2012 European Heart Journal doi:10.1093/eurheartj/ehs092
    • 50. Steno 2 :what reduced the risk ?Steno 2 :what reduced the risk ?
    • 51. Steno 2 “ A watershed study ”Steno 2 “ A watershed study ”
    • 52. THE ACHILES HEELTHE ACHILES HEEL
    • 53. SUMMARY Diabetes is a hydra headedDiabetes is a hydra headed problemproblem Metformin is a poly pill forMetformin is a poly pill for diabetesdiabetes
    • 54. Thank YouThank You
    • 55. ““I have approximate answers and possible beliefsI have approximate answers and possible beliefs in different degrees of certainty about differentin different degrees of certainty about different things, but I am not sure of anything.”things, but I am not sure of anything.” Richard Feyman AmericanRichard Feyman American PhysicistPhysicist

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